WO2006052190A1 - Derives d'indazole sulfonamide - Google Patents

Derives d'indazole sulfonamide Download PDF

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Publication number
WO2006052190A1
WO2006052190A1 PCT/SE2005/001669 SE2005001669W WO2006052190A1 WO 2006052190 A1 WO2006052190 A1 WO 2006052190A1 SE 2005001669 W SE2005001669 W SE 2005001669W WO 2006052190 A1 WO2006052190 A1 WO 2006052190A1
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alkyl
heterocyclyl
cycloalkenyl
aryl
cycloalkyl
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PCT/SE2005/001669
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English (en)
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Vijayaratnam Santhakumar
Miroslaw Tomaszewski
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Astrazeneca Ab
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Priority to US11/718,736 priority Critical patent/US20080004288A1/en
Priority to EP05801477A priority patent/EP1814863A1/fr
Priority to JP2007541137A priority patent/JP2008519833A/ja
Publication of WO2006052190A1 publication Critical patent/WO2006052190A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention is related to therapeutic compounds which are CB 1 receptor ligands, pharmaceutical compositions containg these compounds, manufacturing processes thereof and uses thereof, and more particularly to compounds that are CB 1 receptor agonists. More particularly, the present invention is related to compounds that may be effective in treating pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiavascular disorders.
  • CB 1 receptor e.g., CB 1 receptor, CB 2 receptor
  • ligands including agonists, antagonists and inverse agonists produce relief of pain in a variety of animal models by interacting with CB 1 and/or CB 2 receptors.
  • CB 1 receptors are located predominately in the central nervous system
  • CB 2 receptors are located primarily in the periphery and are primarily restricted to the cells and tissues derived from the immune system.
  • CB 1 receptor agonists such as ⁇ 9 -tetrahydrocannabinol ( ⁇ 9 -THC) and anadamide
  • CNS side-effects e.g., psychoactive side effects, the abuse potential, drug dependence and tolerance, etc.
  • CB 1 receptors located in CNS There are lines of evidence, however, suggesting that CB 1 agonists acting at peripheral sites or with limited CNS exposure can manage pain in humans or animals with much improved overall in vivo profile. Therefore, there is a need for new CB 1 receptor ligands such as agonists, antagonists or inverse agonists that are useful in managing pain or treating other related symptoms or diseases with reduced or minimal undesirable CNS side-effects.
  • the present invention provides CB 1 receptor ligands which are useful in treating pain and other related symptoms or diseases.
  • CB 1 ZCB 2 receptors means CBj and/or CB 2 receptors.
  • C m . n or "C m-n group” used alone or as a prefix, refers to any group having m to n carbon atoms, and having 0 to n multivalent heteroatoms selected from O, S, N and P, wherein m and n are 0 or positive integers, and n>m.
  • C 1-6 would refer to a chemical group having 1 to 6 carbon atoms, and having 0 to 6 multivalent heteroatoms selected from O, S, N and P.
  • hydrocarbon used alone or as a suffix or prefix, refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms.
  • hydrocarbon radical or “hydrocarbyl” used alone or as a suffix or prefix, refers to any structure as a result of removing one or more hydrogens from a hydrocarbon.
  • alkyl used alone or as a suffix or prefix, refers to monovalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms. Unless otherwise specified, “alkyl” general includes both saturated alkyl and unsaturated alkyl.
  • alkylene used alone or as suffix or prefix, refers to divalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms, which serves to links two structures together.
  • alkenyl used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 2 up to : about 12 carbon atoms.
  • alkynyl used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond and comprising at least 2 up to about 12 carbon atoms.
  • cycloalkyl used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms.
  • cycloalkenyl used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 3 up to about 12 carbon atoms.
  • cycloalkynyl used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon triple bond and comprising about 7 up to about 12 carbon atoms.
  • aryl used alone or as suffix or prefix, refers to a monovalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms, wherein the radical is located on a carbon of the aromatic ring.
  • non-aromatic group or “non-aromatic” used alone, as suffix or as prefix, refers to a chemical group or radical that does not containing a ring having aromatic character (e.g., 4n + 2 delocalized electrons).
  • arylene used alone or as suffix or prefix, refers to a divalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms, which serves to links two structures together.
  • heterocycle used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s).
  • Heterocycle may be saturated or unsaturated, containing one or more double bonds, and heterocycle may contain more than one ring. When a heterocycle contains more than one ring, the rings may be fused or unfused. Fused rings generally refer to at least two rings share two atoms therebetween.
  • Heterocycle may have aromatic character or may not have aromatic character.
  • heteroalkyl used alone or as a suffix or prefix, refers to a radical formed as a result of replacing one or more carbon atom of an alkyl with one or more heteroatoms selected from N, O, P and S.
  • heterocyclic used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s), wherein the ring- containing structure or molecule has an aromatic character (e.g., 4n + 2 delocalized electrons).
  • heterocyclic group “heterocyclic moiety,” “heterocyclic,” or
  • heterocyclo used alone or as a suffix or prefix, refers to a radical derived from a heterocycle by removing one or more hydrogens therefrom.
  • heterocyclyl used alone or as a suffix or prefix, refers a monovalent radical derived from a heterocycle by removing one hydrogen from a carbon of a ring of the heterocycle.
  • heterocyclylene used alone or as a suffix or prefix, refers to a divalent radical derived from a heterocycle by removing two hydrogens therefrom, which serves to links two structures together.
  • heteroaryl used alone or as a suffix or prefix, refers to a heterocyclyl having aromatic character, wherein the radical of the heterocyclyl is located on a carbon of an aromatic ring of the heterocyclyl.
  • heterocyclylcoalkyl used alone or as a suffix or prefix, refers to a heterocyclyl that does not have aromatic character.
  • heteroarylene used alone or as a suffix or prefix, refers to a heterocyclylene having aromatic character.
  • heterocycloalkylene used alone or as a suffix or prefix, refers to a heterocyclylene that does not have aromatic character.
  • a five-membered ring heteroaryl is a heteroaryl with a ring having five ring atoms wherein 1, 2 or 3 ring atoms are independently selected from N, O and S.
  • Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4- oxadiazolyl.
  • a six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms wherein 1,
  • Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • substituted used as a prefix refers to a structure, molecule or group, wherein one or more hydrogens are replaced with one or more
  • Q. ⁇ hydrocarbon groups or one or more chemical groups containing one or more heteroatoms selected from N, O, S, F, Cl, Br, I, and P.
  • substituted phenyl may refer to nitrophenyl, pyridylphenyl, methoxyphenyl, chlorophenyl, aminophenyl, etc., wherein the nitro, pyridyl, methoxy, chloro, and amino groups may replace any suitable hydrogen on the phenyl ring.
  • substituted used as a suffix of a first structure, molecule or group, followed by one or more names of chemical groups refers to a second structure, molecule or group, which is a result of replacing one or more hydrogens of the first structure, molecule or group with the one or more named chemical groups.
  • a "phenyl substituted by nitro” refers to nitrophenyl.
  • optionalally substituted refers to both groups, structures, or molecules that are substituted and those that are not substituted.
  • Heterocycle includes, for example, monocyclic heterocycles such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane 2,3-dihydrofuran, 2,5- dihydrofuran tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane, homopiperidine, 2,3,4,7-tetrahydro-lH ⁇ -azepine homopiperaz
  • heterocycle includes aromatic heterocycles, for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, 1,2,3-triazole, tetrazole, 1,2,3- thiadiazole, 1,2,3-oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4- triazole, 1,3,4-thiadiazole, and 1,3,4- oxadiazole.
  • aromatic heterocycles for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, is
  • heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3 -dihydrobenzo furan, isobenzo furan, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine, 1,2- benzisoxazole, benzothiophene, benzox
  • heterocycle includes polycyclic heterocycles wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings.
  • bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane.
  • Heterocyclyl includes, for example, monocyclic heterocyclyls, such as: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydro- pyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3- dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-di
  • heterocyclyl includes aromatic heterocyclyls or heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl.
  • heterocyclyl encompasses polycyclic heterocyclyls (including both aromatic or non-aromatic), for example, indolyl, indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 1,4- benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2,3- dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridin
  • heterocyclyl includes polycyclic heterocyclyls wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings.
  • bridged heterocycles include quinuclidinyl, diazabicyclo[2.2.1]heptyl; and 7-oxabicyclo[2.2.1Jheptyl.
  • alkoxy used alone or as a suffix or prefix, refers to radicals of the general formula — O-R, wherein -R is selected from a hydrocarbon radical.
  • exemplary alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy, and propargyloxy.
  • aryloxy used alone or as suffix or prefix, refers to radicals of the general formula -O-Ar, wherein -Ar is an aryl.
  • heteroaryloxy used alone or as suffix or prefix, refers to radicals of the general formula -O-Ar 1 , wherein -Ar' is a heteroaryl.
  • amine or “amino” used alone or as a suffix or prefix, refers to radicals of the general formula -NRR', wherein R and R' are independently selected from hydrogen or a hydrocarbon radical.
  • Acyl groups include, 'for example, acetyl, propionyl, benzoyl, phenyl acetyl, carboethoxy, and dimethylcarbamoyl.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Halogenated used as a prefix of a group, means one or more hydrogens on the group is replaced with one or more halogens.
  • a first ring group being "fused" with a second ring group means the first ring and the second ring share at least two atoms therebetween.
  • Link means covalently linked or bonded.
  • first group, structure, or atom When a first group, structure, or atom is "directly connected" to a second group, structure or atom, at least one atom of the first group, structure or atom forms a chemical bond with at least one atom of the second group, structure or atom.
  • “Saturated carbon” means a carbon atom in a structure, molecule or group wherein all the bonds connected to this carbon atom are single bond. In other words, there is no double or triple bonds connected to this carbon atom and this carbon atom generally adopts an sp 3 atomic orbital hybridization.
  • Unsaturated carbon means a carbon atom in a structure, molecule or group wherein at least one bond connected to this carbon atom is not a single bond. In other words, there is at least one double or triple bond connected to this carbon atom and this carbon atom generally adopts a sp or sp 2 atomic orbital hybridization.
  • the invention provides a compound of formula I, pharmaceutically acceptable salts thereof, diastereomers, enantiomers, or mixtures thereof:
  • R 1 is selected from hydrogen, Q.ioalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 4 - 8 cycloalkenyl, Ca-iocycloalkyl-C ⁇ ⁇ alkyl, C 4-8 cycloalkenyl- C 1-6 alkyl, C 3-5 heteroaryl, C 6 -ioaryl, C 6 . 10 aryl-C 1-6 alkyl, C 3 .
  • R 2 is selected from hydrogen, C 1-1O aIlCyI, Ca-ioalkenyl, C 2- ioalkynyl, C 3-10 cycloalkyl, C 4- scycloalkenyl, Q.iocycloalkyl-d- ⁇ alkyl, C 4- scycloalkenyl- C 1-6 alkyl, C 3-5 heteroaryl, C 6-1 oaryl, C 6-1O aIyI-C 1 -6 alkyl, C 3-6 heterocycloalkyl, C 3- 6 heterocycloalkyl-C 1-6 alkyl or C 1-6 alkoxycarbonyl; wherein said Q.ioalkyl, C 2 , 10 alkenyl, C2-i O alkynyl, C 3-1 ocycloaU ⁇ yl, C 4 .
  • 6 heterocycloalkyl-C 1-6 alkyl or C 1-6 alkoxycarbonyl used in defining R 2 is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR 4 R 5 ; with one or more substituents selected from C 1-6 alkyl, C 2-6 alkenyl, halogen, C ⁇ alkoxy, amino, cyano, oxo, nitro, hydroxy, C 6-10 aryl, C 6-1 oaryl-d -6alkyl, C 3-6 heterocyclyl and C 3- 6 heterocy cly 1-C 1 -6 alkyl; optionally R 1 and R 2 together with the N to which they are bound may form a 3-10 membered aromatic, heteroaromatic or heterocycloalkyl ring; wherein said aromatic, heteroaromatic or heterocycloalkyl ring is optionally substituted by one or more groups independently selected from
  • R 3 is selected from hydrogen, halogen, amino, C 1-10 alkyl, C 2-1 oalkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-1 ocycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl-C 1 . 6 alkyl, C 3-6 heterocycloalkyl-Ci -6 alkyl, C 4-8 cycloalkenyl, R 4 R 5 N-, C 3-5 heteroaryl, C 6 .
  • aryl and Cs-eheterocycloalkyl used in defining R 3 is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR 4 R 5 ; wherein R 4 and R 5 are independently selected from -H, C 1-6 alkyl, C 2-6 alkenyl,
  • C 2-6 alkynyl, and a divalent C 1-6 group that together with another divalent R 4 or R 5 may form a ring or a portion of a ring wherein said ring is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl and hydroxy; and R 8 is selected from C 3-10 cycloalkyl, C 4- scycloalkenyl, C ⁇ iocycloalkyl-Cu
  • R 8 is optionally substituted by one or more groups selected from hydrogen, Ci. 6 alkyl, C 2-6 alkenyl, halogen, C ⁇ alkoxy, amino, cyano, oxo, nitro, hydroxy and -NR 4 R 5 .
  • the compounds of the present invention are those of formula I, wherein
  • R 1 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2 _ 6 alkynyl, C 3-1 ocycloalkyl, C 4-6 cycloalkenyl, C 3-10 cycloalkyl-Ci -6 alkyl, C 4- scycloalkenyl- Ci -6 alkyl, phenyl, ⁇ henyl-C 1-4 alkyl, C ⁇ eheterocyclyl, C 3-6 heterocyclyl-C 1-6 alkyl or C 1-4 alkoxycarbonyl; wherein said Ci. 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4 .
  • R 2 is selected from hydrogen, Ci. 6 alkyl, C 2 . 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-6 cycloalkenyl, C 4 . 8 cycloalkenyl- C 1-6 alkyl, phenyl, phenyl-C 1-4 alkyl, C 3-6 heterocyclyl, C 3-6 heterocyclyl-C 1-6 alkyl or Ci -4 alkoxycarbonyl; wherein said C 1-6 alkyl, C 2 _ 6 alkenyl, C 2-6 alkynyl, C ⁇ ocycloalkyl, C 4-6 cycloalkenyl, C 3-1 ocycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl-C 1-6 alkyl, phenyl, phenyl-Ci -4 alkyl, C 3-6 heterocyclyl, C 3-6 heterocyclyl-Ci.
  • R 6 alkyl or C 1-4 alkoxycarbonyl used in defining R 2 is optionally substituted by one or more groups selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, Cj -4 alkoxy, amino, oxo, cyano, nitro, hydroxy, C 6- 10 aryl, C ⁇ -ioaryl-C M alkyl, C ⁇ heterocyclyl, C 3-6 heterocyclyl-Ci -4 alkyl and -NR 4 R 5 ;
  • R 1 and R 2 can form together with the N to which they are bound may form a 3-6 membered aromatic, heteroaromatic or heterocycloalkyl ring; wherein said aromatic, heteroaromatic or heterocycloalkyl ring is optionally substituted by one or more groups independently selected from hydrogen, C ⁇ aUcyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, amino, C 1-4 alkoxy, C 1-4 alkoxy-Ci
  • R 3 is selected from hydrogen, halogen, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 4-6 cycloalkenyl, C 3-5 heteroaryl, R 4 R 5 N-, C 3 , 6 cycloalkyl-Ci.
  • R 8 is selected from C 3 . 6 cycloalkyl, C 3-6 cycloalkyl-Ci. 4 alkyl, C 4-6 cycloalkenyl, C 6-1 oaryl, phenyl, phenyl-C 1-4 alkyl, C 3 . 6 heterocyclyl or C 3 .
  • R 1 is selected from hydrogen, C 1-6 alkyL C 2-4 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 4- 6cycloalkenyl, C 4-8 cycloalkenyl-C 1-6 alkyl, C 3 . 8 cycloallcyl-C 1-4 alkyl, phenyl, C 3-6 heterocyclyl, C 3-6 heterocyclyl-Ci -4 alkyl or Ci -2 alkoxycarbonyl; wherein said Ci -6 alkyl, C 2 .
  • R 1 6 heterocyclyl, C 3-6 heterocyclyl-Ci -4 alkyl or C 1-2 alkoxycarbonyl used in defining R 1 is optionally substituted with one or more groups selected from Q ⁇ alkyl, halogen, C ⁇ alkoxy, amino, cyano, oxo, hydroxy, C 3-6 heterocyclyl, C 3-6 heterocyclyl- C 1-4 alkyl, C 6-8 aryl, C6-8aryl-C 1-4 alkyl;
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 2 - 4 alkeiiyl, C 2-6 alkynyl,
  • cycloalkyl-C 1-4 alkyl, phenyl, phenyl- C 1-4 alkyl, Cs- ⁇ heterocyclyl, C 3-6 heterocyclyl-Ci -4 alkyl or Ci -2 alkoxycarbonyl used in defining R 2 is optionally substituted with one or more groups selected from C 1-4 alkyl, halogen, C 1-4 alkoxy, amino, cyano, oxo, hydroxy, C 3-6 heterocyclyl, C 3-6 heterocyclyl- C 1-4 alkyl, C 6- saryl, C 6 . 8 aryl-C 1-4 alkyl;
  • R 1 and R 2 together with the N to which they are bound may form a group selected from 1,2,3,6-tetrahydro-pyridinyl, 1,2,3-oxadiazolyl, 1,2,3- thiadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4- triazolyl, 1,3,4- oxadiazolyl, 1,3,4-thiadiazolyl, 1,3,4-triazolyl, 1,3-dioxanyl, 1,3-dioxepanyl, 1,4-benzodioxanyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 2,3,4,7- tetrahydro-lH-azepinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrofuranyl, 2,3- dihydropyranyl, 2,5-dihydrofuranyl, 4,
  • R 3 is selected from hydrogen, halogen, amino, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 CyClOaIlSyI, C 3 , 6 cycloalkyl-C 1-4 alkyl, C 3-6 heterocyclyl or C 3-6 heterocyclyl-C 1-4 alkyl wherein said amino, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C 3 .6cycloalkyl-C 1-4 alkyl, C 3-6 heterocyclyl or C ⁇ heterocyclyl-C M alkyl used in defining R 3 is optionally substituted with one or more groups selected from Ci.
  • C 2-4 alkynyl and a divalent C 1-4 group that together with another divalent R 4 or R 5 may form a ring or a portion of a ring; wherein said ring is optionally substituted by one or more groups selected from methoxy, ethoxy, methyl, ethyl and hydroxy; and
  • R is selected from phenyl, allyl, phenyl-C 1-4 alkyl, C 3 . 6 cycloalkyl-C 1-4 alkyl, C 4-6 cycloalkenyl-C 1-4 alkyl, Cs- ⁇ heterocycloalkyl, Cs.
  • R 8 ⁇ heterocylcoalkyl-C ⁇ ⁇ alkyl, C 6- ioaryl, C 3-6 CyClOaIlCyI 5 and C 4-6 cycloalkenyl, wherein said phenyl, phenyl-Ci -4 alkyl, C 3-6 Cy cloalkyl-C 1-4 alkyl, C 4-6 cycloalkenyl-C 1-4 allcyl, C ⁇ heterocycloalkyl, C 3- 6 heterocylcoalkyl-C 1-4 alkyl, C 6-1 oaryl, C 3-6 cycloalkyl, and C 4-6 cycloalkenyl, used in defining R 8 is optionally substituted by one or more groups selected from C 1-4 alkyl, d ⁇ alkoxy, halogen, amino, cyano, oxo, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR 4 R 5 .
  • the compounds of the present invention are those of formula I, wherein R is selected from hydrogen, methyl, ethyl, propyl, n-butyl, t-butyl, n-pentyl, t-pentyl, hexyl, propenyl, bute ⁇ yl, cyclopropyl, cyclopentyl.
  • eyclohexyl cyclopropylmethyl, cyclohexylmethyl, tetrahydrothiophenyl, phenyl, phenylmethyl, 2-phenylethyl, pyrimidinyl, furanylmethyl, pyridinylmethyl, pyrazinylmethyl or methoxycarbonyl; wherein the ethyl, propyl, n-butyl, t-butyl, n-pentyl, t-pentyl, hexyl, propenyl, butenyl, cycloproply, cyclopentyl, eyclohexyl, cyclopropylmethyl, cyclohexylmethyl, tetrahydrothiophenyl, phenyl, phenylmethyl, 2-phenylethyl, pyrimidinyl, furanylmethyl, pyridinylmethyl, pyrazinylmethyl or methoxycarbonyl
  • R is selected from hydrogen, methyl, ethyl, propyl, n-butyl, t-butyl, n-pentyl, t-pentyl, hexyl, propenyl, butenyl, cycloproply, cyclopentyl, eyclohexyl, cyclopropylmethyl, cyclohexylmethyl, tetrahydrothiophenyl, phenyl, phenylmethyl, 2-phenylethyl, pyrimidinyl, furanylmethyl, pyridinylmethyl, pyrazinylmethyl or methoxycarbonyl; wherein the ethyl, propyl, n-butyl, t-butyl, n-pentyl, t-pentyl, hexyl, propenyl, butenyl, cycloproply, cyclopentyl, cyclohexyl, cycloprop
  • R 1 and R 2 together with the N to which they are bound may form a group selected from cylcohexyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, piperazinyl or morpholinyl; wherein said cylcohexyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, piperazinyl or morpholinyl used in defining R 1 and R 2 together is optionally substituted by one or more groups selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, hydrogen, halogen, amino, C 1-4 alkoxy, C 1-4 alkoxy-C 1-2 alkyl, Q ⁇ alkoxycarbon
  • R 3 is selected from hydrogen, Cl, diethylamino, cyclohexylmethylamino, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, t-butyl, n-butyl, 2-methyl-2- butyl, isopentyl, 2-methoxy-2-propyl, 2-hydroxyl-propyl, 1-methyl-propyl, 1,1- dimethyl-propyl, l,l-dimethyl-3-buten-l-yl, ethyl, 2-propyl and -NR 4 R 5 ; wherein said diethylamino, cyclohexylmethylamino, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, t-butyl, n-butyl, 2-methyl-2-butyl, isopentyl, 2-methoxy- 2-pro ⁇ yl, 2-hydroxyl-propyl, 1-methyl-propy
  • R 4 alkenyl, C 2-4 alkynyl, and a divalent C 1-4 group that together with another divalent R 4 or R 5 may form a group selected from morpholinyl and piperazinyl; wherein said morpholinyl and piperazinyl is optionally substituted by one or more groups selected from methoxy, ethoxy, methyl, ethyl and hydroxy; and R 8 is selected from phenyl, allyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, tetrahydrofuranyl, 1- piperidinyl, N-methyl-2-piperidinyl and benzyl; wherein said phenyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopenty
  • the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture.
  • the present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I.
  • the optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter.
  • certain compounds of the present invention may exist as geometrical isomers, for example E and Z isomers of alkenes.
  • the present invention includes any geometrical isomer of a compound of Formula I. It will further be understood that the present invention encompasses tautomers of the compounds of the formula I.
  • salts of the compounds of the formula I are also salts of the compounds of the formula I.
  • pharmaceutically acceptable salts of compounds of the present invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCl or acetic acid, to afford a physiologically acceptable anion.
  • a corresponding alkali metal such as sodium, potassium, or lithium
  • an alkaline earth metal such as ' a calcium
  • a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques.
  • a suitably acidic proton such as a carboxylic acid or a phenol
  • an alkali metal or alkaline earth metal hydroxide or alkoxide such as the ethoxide or methoxide
  • a suitably basic organic amine such as choline or meglumine
  • the compound of formula I above may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or p-toluenesulphonate.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or p-toluenesulphonate.
  • the compounds of the invention exhibit selective activity as agonist of the CBl receptors and are useful in therapy, especially for relief of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pairi caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive. Additionally, compounds of the present invention are useful in other disease states in which dysfunction of the CBl receptor is present or implicated. Furthermore, the compounds of the invention may be used to treat cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiavascular disorders.
  • Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents.
  • Compounds of the invention are useful in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
  • PET positron emission tomography
  • Compounds of the invention are useful for the treatment of diarrhoea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive - Ig - compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, e.g.
  • constipation functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury, stroke, cardioprotection following miocardial infarction, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
  • functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia
  • Parkinson's disease and other motor disorders traumatic brain injury, stroke, cardioprotection following miocardial infarction
  • spinal injury and drug addiction including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
  • Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care.
  • Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.
  • a further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby ari effective amount of a compound according to the formula I above, is administered to a patient in need of such treatment.
  • the invention provides a compound of formula I, or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
  • the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the term “therapeutic” and “therapeutically” should be contrued accordingly.
  • the term “therapy” within the context of the present invention further encompasses to administer an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition.
  • This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.
  • the compounds of the present invention are useful in therapy, especially for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, acute pain, back pain, cancer pain, and visceral pain.
  • the compound of the invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasaliy, intraperitoneal ⁇ , intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
  • the route of administration may be orally, intravenously or intramuscularly.
  • inert, pharmaceutically acceptable carriers can be either solid and liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or table disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided compound of, the invention, or the active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture in then poured into convenient sized moulds and allowed to cool and solidify.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
  • Tlie term composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it.
  • a carrier which is thus in association with it.
  • cachets are included. Tablets, powders, cachets, and capsules can be used as sd ⁇ id dosage forms suitable for oral administration.
  • Liquid form compositions include solutions, suspensions, and emulsions.
  • sterile water or water propylene glycol solutions of. the active compounds may be liquid preparations suitable for parenteral administration.
  • Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical composition will preferably include from 0.05% to 99%w (per cent by weight), more preferably from 0.10 to 50%w, of the compound of the invention, all percentages by weight being based on total composition.
  • a therapeutically effective amount for the practice of the present invention may be determined, by the use of known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented, by one of ordinary skills in the art.
  • any compound according to Formula I for the manufacture of a medicament for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, acute pain, back pain, cancer pain, and visceral pain.
  • a further aspect of the invention is a method for therapy of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such therapy.
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for therapy, more particularly for therapy of pain.
  • composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the conditions discussed above.
  • the present invention provides a method of preparing the compounds of the present invention.
  • the invention provides a process for preparing a compound of Formula II, comprising of the step of
  • R 1 is selected from hydrogen, Ci.iQalkyl, C 2-10 alkenyl, C 2-10 alkynyl,
  • 6 heterocycloalkyl, C 3-6 heterocycloalkyl-C 1-6 alkyl or C 1-6 alkoxycarbonyl used in defining R 2 is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR 4 R 5 ; with one or more substituents selected from Ci -6 alkyl, C 2 - 6 alkenyl, halogen, C 1-6 alkoxy, amino, cyano, oxo, nitro, hydroxy, C 6-1 oaryl, C 6-10 aryl-Ci -6 alkyl, C 3-6 heterocyclyl and C 3- 6 heterocy clyl-C i -6 alkyl;
  • R 2 is selected from hydrogen, C 1-10 alkyl, C 2-1 oalkenyl, C 2-10 alkynyl, C 3-1 ocycloalkyl, C4-scycloalkenyl, C 4-8 cycloalkenyl- C 1-6 alkyl, C 3 .
  • R 2 10 aryl, C 6-10 aryl-C 1-6 alkyl, C 3- 6 heterocycloalkyl, or C ⁇ galkoxycarbonyl used in defining R 2 is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR 4 R 5 ; with one or more substituents selected from amino, cyano, oxo, nitro, hydroxy, C 6-10 aryl, C ⁇ -ioaryl-Q- ⁇ alkyl, C 3-6 heterocyclyl and C 3- 6 heterocyclyl-C 1-6 alkyl; optionally R 1 and R 2 together with the N to which they are bound may form a 3-10 membered aromatic, heteroaromatic or heterocycloalkyl ring; wherein said aromatic, heteroaromatic or heterocycloalkyl ring is optionally substituted by one or more groups independently selected from hydrogen, C 1-6 alkyl,
  • R 3 is selected from hydrogen, halogen, amino, Ci. 10 alkyl, C 2- i 0 alkenyl, C 2- ioalkynyl, C 3-10 cycloalkyl, C 3-1 ocycloalkyl-C 1-6 alkyl, C 4- scycloalkenyl-Ci -6 alkyl, Cs.eheterocycloalkyl-C ⁇ gallcyl, C 4- scycloalkenyL R 4 R 5 N-, C 3-5 heteroaryl, C 6-10 aryl and Cs.
  • heterocycloalkyl wherein said amino, Cuioalkyl, C 2-1 oalkenyl, C 2-1 oalkynyl, C 3- iocycloalkyl, C 3-1 ocycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl-C 1-6 alkyl, Cs-eheterocycloalkyl-Q-fjalkyl, C 4- scycloalkenyl, R 4 R 5 N-, C 3-5 heteroaryl, C 6 .ioaryl and Q-eheterocycloalkyl used in defining R 3 is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR 4 R 5 ; wherein R 4 and R 5 are independently selected from — H, Ci -6 alkyl, C 2 .
  • Further embodiments of the invention provide a process for preparing the compounds of the invention according to the synthetic routes depicted in the general procedures below:
  • R 4-Fuorophenylmethyt 2,6-Dichlorophenyimethyi Phenytmethyl 3-Chlorophenylmethyl 2-Fluorophenylmetriyl 2-Trifiuoromethyfphenyfmethyl Phenyl AIIyI
  • R 4-Fluorophenylmethyl 2,6-Dichlorophenylmethyl Phenylmethyl
  • R 1 R 2 NH, 3-Chlorophenylmethyl Et 3 N, DCE
  • Human CB 1 receptor from Receptor Biology (hCBl) or human CB 2 receptor from BioSignal (hCB2) membranes are thawed at 37 0 C, passed 3 times through a 25- gauge blunt-end needle, diluted in the cannabinoid binding buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl 2 , and 0.5 mg/mL BSA fatty acid free, pH 7.4) and aliquots containing the appropriate amount of protein are distributed in 96-well plates.
  • cannabinoid binding buffer 50 mM Tris, 2.5 mM EDTA, 5 mM MgCl 2 , and 0.5 mg/mL BSA fatty acid free, pH 7.4
  • the IC 50 of the compounds of the invention at 11CB 1 and hCB 2 are evaluated from 10-point dose-response curves done with 3 H-CP55,940 at 20000 to 25000 dpm per well (0.17- 0.21 nM) in a final volume of 300 ⁇ l.
  • the total and non-specific binding are determined in the absence and. presence of 0.2 ⁇ M of HU210 respectively.
  • the plates are vortexed and incubated for 60 minutes at room temperature, filtered through Unifilters GF/B (presoaked in 0.1% polyethyleneimine) with the Tomtec or Packard harvester using 3 mL of wash buffer (50 mM Tris, 5 mM MgCl 2 , 0.5 mg BSA pH 7.0). The filters are dried for 1 hour at 55 0 C.
  • the radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 ⁇ l/well of MS-20 scintillation liquid.
  • Human CBi receptor from Receptor Biology (hCBl) or human CB 2 receptor membranes (BioSignal) are thawed at 37 0 C, passed 3 times through a 25-gauge blunt-end needle and diluted in the GTP ⁇ S binding buffer (50 mM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl 2 , pH 7.4, 0.1% BSA).
  • the EC 50 and E ma ⁇ of the compounds of the invention are evaluated from 10-point dose- response curves done in 300 ⁇ l with the appropriate amount of membrane protein and 100000-130000 dpm of GTPg 35 S per well (0.11 -0.14 nM).
  • the basal and maximal stimulated binding is determined in absence and presence of 1 ⁇ M (hCB 2 ) or 10 ⁇ M (hCBi) Win 55,212-2 respectively.
  • the membranes are pre-incubated for 5 minutes with 56.25 ⁇ M (hCB2) or 112.5 ⁇ M (!1CB 1 ) GDP prior to distribution in plates (15 ⁇ M (hCB 2 ) or 30 ⁇ M QxCBi) GDP final).
  • the plates are vortexed and incubated for 60 minutes at room temperature, filtered on Unif ⁇ lters GF/B (presoaked in water) with the Tomtec or Packard harvester using 3 ml of wash buffer (50 mM Tris, 5 mM MgCl 2 , 50 mM NaCl, pH 7.0). The filters are dried for 1 hour at 55 °C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 ⁇ l/well of MS-20 scintillation liquid.
  • wash buffer 50 mM Tris, 5 mM MgCl 2 , 50 mM NaCl, pH 7.0.
  • the filters are dried for 1 hour at 55 °C.
  • the radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 ⁇ l/well of MS-20 scintillation liquid.
  • Antagonist reversal studies are done in the same way except that (a) an agonist dose-response curve is done in the presence of a constant concentration of antagonist, or (b) an antagonist dose-response curve is done in the presence of a constant concentration of agonist.
  • the dissociation constant (Ki) for a particular compound of the invention towards a particular receptor is determined using the following equation:
  • Ki IC 50 /(l+[rad]/Kd)
  • IC 5O is the concentration of the compound of the invention at which 50% displacement has been observed
  • [rad] is a standard or reference radioactive ligand concentration at that moment
  • Kd is the dissociation constant of the radioactive ligand towards the particular receptor.
  • the Ki towards human CB 1 receptors for most compounds of the invention is measured to be in the range of 36-5700 nM.
  • the Ki towards human CB 2 receptors for most compounds of the invention is measured to be in the range of about 1.6-36 nM.
  • Step A 3-chIoro-l-(4-fluoroben2yI)-i ⁇ yV-dipropyl-li ⁇ -indazole-5-sulfonamide
  • Step A l-[(3-chloropIienyl)methyl]- ⁇ ? -[3-(dimethylamino)propyl]-3-(l- pyrrolidinyl)-lH-indazole-5-sulfonamide
  • Step B l-[(3-chlorophenyl)methyl]-3-(l-pyrrolidinyl)-li3-indazole
  • Step A iV-(cyclopropylmethyl)-3-(diethylamino)-l-[(4-fluorophenyl)methyl]-iV- propyl-lJ ⁇ -indazole-5-sulfonamide
  • Step B i ⁇ VV-diethyl-l-[(4-fluorophenyl)methyl]-lH-indazoI-3-amine
  • Step A 4-[[l-[(2,6-dichlorophenyl)methyl]-3-(diethylamino)-lJ3 r -indazol-5- yl]sulfbnyl] ⁇ , 1-piperazinecarboxylic acid, ethyl ester
  • Step B l-[(2,6-dichlorophenyl)methyl]- ⁇ yV-diethyl-lJ ⁇ -mdazol-3-arame
  • Step A l-(4-fluorobenzyl)-3-(4-methyIpiperazin-l-yl)-iVyV-dipropyl-lH- indazole-5-sulfonamide
  • the crude product was purified by silica gel column chromatography.
  • the free base of the title compound was obtained as crystals from methanol.
  • a solution of HCl in diethylether (3 equiv.) was added to a solution of the free base in dichloromethane (20 ml/mmol).
  • the solution was stirred at room temperature for 15 minutes and concentrated in vacuo.
  • the residue was dissolved in dioxan and lyophylized to yield the title compound as the HCl salt.
  • flash chromatography (3:97 methanol: dichloromethane)
  • the title compound 140mg, 81%) was obtained as a pale yellow solid.
  • Step B 3-chloro-l-(4-fluoroben2yl)-i ⁇ yV-dipropyl-ljH-indazole-5-sulfonamide
  • step A after flash chromatography (5:95 methanol: dichloromethane), the title compound (74 mg, 55%) was obtained as a pale yellow solid.

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Abstract

L'invention concerne la préparation de composés de formule I ou des sels acceptables sur le plan pharmaceutique de ceux-ci: dans laquelle R1, R2, R3 et R8 sont tels que définis dans la description, ainsi que des sels et des compositions pharmaceutiques renfermant les composés. Ces composés sont utiles dans un traitement, notamment dans le soulagement de la douleur.
PCT/SE2005/001669 2004-11-11 2005-11-07 Derives d'indazole sulfonamide WO2006052190A1 (fr)

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US11/718,736 US20080004288A1 (en) 2004-11-11 2005-11-07 Indazole Sulphonamide Derivatives
EP05801477A EP1814863A1 (fr) 2004-11-11 2005-11-07 Derives d'indazole sulfonamide
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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2056828A2 (fr) * 2006-08-21 2009-05-13 Merck & Co., Inc. Pipérazines sulfonylées en tant que modulateurs du récepteur de cannabinoïde-1
JP2011503080A (ja) * 2007-11-07 2011-01-27 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｂ２受容体を調節する化合物
EP2448581A1 (fr) * 2009-06-29 2012-05-09 Agios Pharmaceuticals, Inc. Compositions thérapeutiques et procédés d'utilisation associés
WO2014026330A1 (fr) * 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. Composés 3-aminocycloalkyles en tant qu'inhibiteurs de rorgammat et leurs utilisations
US8742119B2 (en) 2009-04-06 2014-06-03 Agios Pharmaceuticals, Inc. Pyruvate kinase M2 modulators, therapeutic compositions and related methods of use
US8785450B2 (en) 2009-06-29 2014-07-22 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US8889667B2 (en) 2010-12-29 2014-11-18 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
US9181231B2 (en) 2011-05-03 2015-11-10 Agios Pharmaceuticals, Inc Pyruvate kinase activators for use for increasing lifetime of the red blood cells and treating anemia
US9221792B2 (en) 2010-12-17 2015-12-29 Agios Pharmaceuticals, Inc N-(4-(azetidine-1-carbonyl) phenyl)-(hetero-) arylsulfonamide derivatives as pyruvate kinase M2 (PMK2) modulators
EP2911663A4 (fr) * 2012-10-26 2016-04-13 Merck Sharp & Dohme Composés indazole sulfonamide n-substitués ayant une activité sélective dans les canaux sodiques potentiel-dépendants
US9328077B2 (en) 2010-12-21 2016-05-03 Agios Pharmaceuticals, Inc Bicyclic PKM2 activators
US9365545B2 (en) 2013-03-15 2016-06-14 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
WO2016097391A1 (fr) * 2014-12-19 2016-06-23 Galderma Research & Development Dérivés indazoles sulfonamides en tant qu'agonistes inverses du récepteur gamma orphelin associé aux rétinoïdes ror gamma (t)
US9603838B2 (en) 2011-02-11 2017-03-28 Merck Sharp & Dohme Corp. RORgammaT inhibitors
US9745265B2 (en) 2012-08-15 2017-08-29 Merck Sharp & Dohme Corp. 4-heteroaryl substituted benzoic acid compounds as RORgammaT inhibitors and uses thereof
US9980961B2 (en) 2011-05-03 2018-05-29 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US10221142B2 (en) 2015-02-11 2019-03-05 Merck Sharp & Dohme Corp. Substituted pyrazole compounds as RORgammaT inhibitors and uses thereof
US10287272B2 (en) 2015-10-27 2019-05-14 Merck Sharp & Dohme Corp. Substituted indazole compounds as RORgammaT inhibitors and uses thereof
US10344000B2 (en) 2015-10-27 2019-07-09 Merck Sharp & Dohme Corp. Substituted bicyclic pyrazole compounds as RORgammaT inhibitors and uses thereof
US10457637B2 (en) 2014-12-19 2019-10-29 Galderma Research & Development Benzenesulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma (RORγ(T))
US10584121B2 (en) 2015-10-27 2020-03-10 Merck Sharp & Dohme Corp. Heteroaryl substituted benzoic acids as RORgammaT inhibitors and uses thereof
US11234976B2 (en) 2015-06-11 2022-02-01 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators
WO2022117882A3 (fr) * 2020-12-03 2022-07-07 Domain Therapeutics Nouveaux inhibiteurs de par-2

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015127125A1 (fr) * 2014-02-20 2015-08-27 Cornell University Composés et procédés d'inhibition de la fascine
WO2023186058A1 (fr) * 2022-03-31 2023-10-05 江苏恒瑞医药股份有限公司 Composé d'indazole, son procédé de préparation et son utilisation en médecine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040116465A1 (en) * 2001-04-20 2004-06-17 Yun-Xing Cheng Novel compounds

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1795227A1 (de) * 1968-08-24 1971-11-04 Basf Ag Neue basische Azofarbstoffe der Indazolreihe
DE2653005A1 (de) * 1975-12-03 1977-06-08 Sandoz Ag Neue organische verbindungen, ihre verwendung und herstellung
US4981613A (en) * 1986-11-04 1991-01-01 Fuji Photo Film Co., Ltd. Laser light source
US5378714A (en) * 1991-11-27 1995-01-03 Novo Nordisk A/S Antipsychotic piperidine derivatives
US5612360A (en) * 1992-06-03 1997-03-18 Eli Lilly And Company Angiotensin II antagonists
US5760246A (en) * 1996-12-17 1998-06-02 Biller; Scott A. Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method
IL144910A0 (en) * 1999-04-15 2002-06-30 Bristol Myers Squibb Co Cyclic compounds and pharmaceutical compositions containing the same
FR2836914B1 (fr) * 2002-03-11 2008-03-14 Aventis Pharma Sa Indazoles substitues, compositions les contenant, procede de fabrication et utilisation
EP1750696B1 (fr) * 2004-05-07 2013-06-26 Sequoia Pharmaceuticals Inc Inhibiteurs de protéase rétrovirale repoussant leur résistance

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040116465A1 (en) * 2001-04-20 2004-06-17 Yun-Xing Cheng Novel compounds

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EP2056828A4 (fr) * 2006-08-21 2010-06-23 Merck Sharp & Dohme Pipérazines sulfonylées en tant que modulateurs du récepteur de cannabinoïde-1
EP2056828A2 (fr) * 2006-08-21 2009-05-13 Merck & Co., Inc. Pipérazines sulfonylées en tant que modulateurs du récepteur de cannabinoïde-1
JP2011503080A (ja) * 2007-11-07 2011-01-27 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｂ２受容体を調節する化合物
US8742119B2 (en) 2009-04-06 2014-06-03 Agios Pharmaceuticals, Inc. Pyruvate kinase M2 modulators, therapeutic compositions and related methods of use
US9938259B2 (en) 2009-04-06 2018-04-10 Agios Pharmaceuticals, Inc. Therapeutic compositions and related methods of use
US9657004B2 (en) 2009-04-06 2017-05-23 Agios Pharmaceuticals, Inc Pyruvate kinase M2 modulators, therapeutic compositions and related methods of use
EP2448581B1 (fr) * 2009-06-29 2016-12-07 Agios Pharmaceuticals, Inc. Compositions thérapeutiques et procédés d'utilisation associés
EP2448581A1 (fr) * 2009-06-29 2012-05-09 Agios Pharmaceuticals, Inc. Compositions thérapeutiques et procédés d'utilisation associés
US9115086B2 (en) 2009-06-29 2015-08-25 Agios Pharmaceuticals, Inc. Therapeutic compositions and related methods of use
US11866411B2 (en) 2009-06-29 2024-01-09 Agios Pharmaceutical, Inc. Therapeutic compounds and compositions
US8785450B2 (en) 2009-06-29 2014-07-22 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
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US10029987B2 (en) 2009-06-29 2018-07-24 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US9221792B2 (en) 2010-12-17 2015-12-29 Agios Pharmaceuticals, Inc N-(4-(azetidine-1-carbonyl) phenyl)-(hetero-) arylsulfonamide derivatives as pyruvate kinase M2 (PMK2) modulators
US10087169B2 (en) 2010-12-21 2018-10-02 Agios Pharmaceuticals, Inc. Bicyclic PKM2 activators
US9328077B2 (en) 2010-12-21 2016-05-03 Agios Pharmaceuticals, Inc Bicyclic PKM2 activators
US9199968B2 (en) 2010-12-29 2015-12-01 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US8889667B2 (en) 2010-12-29 2014-11-18 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
US9603838B2 (en) 2011-02-11 2017-03-28 Merck Sharp & Dohme Corp. RORgammaT inhibitors
US9884043B2 (en) 2011-02-11 2018-02-06 Merck Sharp & Dohme Corp. RORgammaT inhibitors
US9980961B2 (en) 2011-05-03 2018-05-29 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US11793806B2 (en) 2011-05-03 2023-10-24 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US10632114B2 (en) 2011-05-03 2020-04-28 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US9181231B2 (en) 2011-05-03 2015-11-10 Agios Pharmaceuticals, Inc Pyruvate kinase activators for use for increasing lifetime of the red blood cells and treating anemia
US9745265B2 (en) 2012-08-15 2017-08-29 Merck Sharp & Dohme Corp. 4-heteroaryl substituted benzoic acid compounds as RORgammaT inhibitors and uses thereof
WO2014026330A1 (fr) * 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. Composés 3-aminocycloalkyles en tant qu'inhibiteurs de rorgammat et leurs utilisations
EP2920149A4 (fr) * 2012-08-15 2016-07-27 Merck Sharp & Dohme Composés 3-aminocycloalkyl utilisés en tant qu'inhibiteurs de rorgammat et utilisations de ceux-ci
US10196354B2 (en) 2012-08-15 2019-02-05 Merck Sharp & Dohme Corp. 4-heteroaryl substituted benzoic acid compounds as RORgammaT inhibitors and uses thereof
US9663522B2 (en) 2012-08-15 2017-05-30 Merck Sharp & Dohme Corp. 3-aminocycloalkyl compounds as RORgammaT inhibitors and uses thereof
WO2014028600A2 (fr) 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. Composés 3-aminocycloalkyl utilisés en tant qu'inhibiteurs de rorgammat et utilisations de ceux-ci
EP2911663A4 (fr) * 2012-10-26 2016-04-13 Merck Sharp & Dohme Composés indazole sulfonamide n-substitués ayant une activité sélective dans les canaux sodiques potentiel-dépendants
US9365545B2 (en) 2013-03-15 2016-06-14 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
US10246440B2 (en) 2014-12-19 2019-04-02 Galderma Research & Development Indazole sulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma (ROR γ (T))
US10457637B2 (en) 2014-12-19 2019-10-29 Galderma Research & Development Benzenesulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma (RORγ(T))
US10550110B2 (en) 2014-12-19 2020-02-04 Galderma Research & Development Tetrahydroquinoline sulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma (ROR gamma (t))
US10618890B2 (en) 2014-12-19 2020-04-14 Galderma Research & Development Benzimidazole sulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma (ROR gamma (T))
WO2016097391A1 (fr) * 2014-12-19 2016-06-23 Galderma Research & Development Dérivés indazoles sulfonamides en tant qu'agonistes inverses du récepteur gamma orphelin associé aux rétinoïdes ror gamma (t)
US10752617B2 (en) 2014-12-19 2020-08-25 Galderma Research & Development Indazole sulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma (ROR gamma (T))
US10221142B2 (en) 2015-02-11 2019-03-05 Merck Sharp & Dohme Corp. Substituted pyrazole compounds as RORgammaT inhibitors and uses thereof
US11234976B2 (en) 2015-06-11 2022-02-01 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators
US10689369B2 (en) 2015-10-27 2020-06-23 Merck Sharp & Dohme Corp. Substituted indazole compounds as RORgammaT inhibitors and uses thereof
US10584121B2 (en) 2015-10-27 2020-03-10 Merck Sharp & Dohme Corp. Heteroaryl substituted benzoic acids as RORgammaT inhibitors and uses thereof
US10344000B2 (en) 2015-10-27 2019-07-09 Merck Sharp & Dohme Corp. Substituted bicyclic pyrazole compounds as RORgammaT inhibitors and uses thereof
US10287272B2 (en) 2015-10-27 2019-05-14 Merck Sharp & Dohme Corp. Substituted indazole compounds as RORgammaT inhibitors and uses thereof
WO2022117882A3 (fr) * 2020-12-03 2022-07-07 Domain Therapeutics Nouveaux inhibiteurs de par-2

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US20080004288A1 (en) 2008-01-03

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